Rheumatoid arthritis (RA) is an important health problem, causing significant pain, disability and financial burden. Unfortunately, its etiology and pathogenesis remain enigmatic, restricting the rational choice of therapeutic strategies. Appreciation of a crucial role for B cells and the antibodies they produce has waxed and waned over the years but, of late, these players have moved back into the limelight, primarily because of the recent positive clinical results using anti-CD20. The K/BxN mouse model of inflammatory arthritis highlights the role of B cells and antibodies. Particularly convenient is an adaptation wherein transfer of serum from arthritic mice into normal recipients rapidly, robustly and repeatedly induces arthritis. Preliminary data indicate that engagement of Toll-like receptors (TLRs) by pathogen-associated molecule patterns can have a striking positive or negative impact on K/BxN serum-transferred arthritis. In particular, injection of certain CpG-containing oligodeoxynucleotides (ODNs) in either a preventive or therapeutic mode inhibits arthritis development or progression. This is an early effect, exerting its impact between the characteristic opening of the vasculature and initiation of the inflammatory cascade signaled by immune complex deposition, complement activation and leukocyte invasion. It requires interleukin-12p35, interferon (IFN)-gamma and TLR9, and also appears to depend on both natural killer and dendritic cells. The CpG-mediated inhibitory effect is mimicked by systemic injection of IFN-gamma. It operates in the prototypical C57BI/6 strain, but not in the Balb/c. Here we propose to explore the cellular and molecular mechanisms underlying CpG-promoted protection from K/BxN serum-transferred arthritis, and to dissect genetic influences on them. More specifically, we aim to: Determine how ODN1668 promotes IFN-gamma production, Elucidate events downstream of IFN-gamma production, Determine why Balb/c mice resist the inhibitory effect of ODN1668. An encouraging performance by recombinant human IFN-gamma in several small clinical trials on RA patients in the 1980s and 1990s suggests that results from the studies proposed may have validity in the human system, despite some known differences in TLR expression and downstream elements.